Method of induction of apoptosis and inhibition of matrix metalloproteinases using antimicrobial metals

Abstract

The invention relates to a method to induce apoptosis and to inhibit matrix metalloproteinases in a disease condition in a human or animal by contacting hyperplastic tissue, tumor tissue, or a cancerous lesion with one or more antimicrobial metals, preferably formed with atomic disorder, and preferably in a nanocrystalline form. In another aspect of the invention, there is provided a method of preventing excessive release of matrix metalloproteinases from an inflammatory cell in a disease condition in a human or an animal by contacting the cell with a therapeutically effective amount of a noble metal in a crystalline form characterized by atomic disorder, or with a solution derived therefrom to provide a modulatory effect on one or more matrix metalloproteinases, wherein the one or more noble metals is formed with atomic disorder, and preferably in a nanocrystalline form. The nanocrystalline antimicrobial or noble metal of choice may be used in the form of a nanocrystalline coating of one or more antimicrobial or noble metals, a nanocrystalline powder of one or more antimicrobial or noble metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more antimicrobial or noble metals.

We claim: 
     
       1. A method of treating excessive release of one or more matrix metalloproteinases from an inflammatory cell in a disease condition in a human or an animal, which comprises:
 contacting the cell with a therapeutically effective amount of a noble metal in a crystalline form characterized by atomic disorder, or with a solution derived therefrom, to provide a modulating effect on one or more matrix metalloproteinases, wherein the noble metal is formed with sufficient atomic disorder, such that the metal, in contact with an alcohol or water-based electrolyte, releases atoms, ions, molecules, or clusters of at least one noble metal at a concentration sufficient to provide a localized anti-MMP effect. 
 
     
     
       2. The method according to  claim 1 , further comprising providing a modulating effect on one or more cytokines. 
     
     
       3. The method as set forth in  claim 2 , wherein the noble metal is silver. 
     
     
       4. The method as set forth in  claim 3 , wherein the noble metal is nanocrystalline and is formed with sufficient atomic disorder such that, in contact with an alcohol or water based electrolyte, the noble metal releases ions, atoms, molecules or clusters of the noble metal on a sustainable basis. 
     
     
       5. The method as set forth in  claim 4 , wherein the one or more matrix metalloproteinases are selected from the group consisting of collagenases, gelatinases, stromelysins, and stromelysin-like matrix metalloproteinases. 
     
     
       6. The method as set forth in  claim 5 , wherein the one or more matrix metalloproteinases is a gelatinase. 
     
     
       7. The method as set forth in  claim 6 , wherein the gelatinase is MMP-9. 
     
     
       8. The method as set forth in  claim 7 , wherein the cytokine is TNF-α. 
     
     
       9. The method as set forth in  claim 8 , wherein the noble metal is nanocrystalline silver. 
     
     
       10. The method as set forth in  claim 8 , wherein the noble metal is silver, formed as a composite with oxygen. 
     
     
       11. The method as set forth in  claim 8 , wherein the one or more noble metals are provided as a coating on, or filler in, a dressing or a hydrated dressing, or in a pharmaceutical composition with one or more pharmaceutically and dermatogically acceptable carriers, diluents, or excipients suitable for topical application. 
     
     
       12. The method as set forth in  claim 11 , wherein the pharmaceutical composition includes a nanocrystalline powder of one or more noble metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more noble metals. 
     
     
       13. The method as set forth in  claim 12 , wherein the pharmaceutical composition is a gel, cream, lotion, paste, or ointment containing the noble metal powder in an amount of 0.01–10% by weight, or a liquid formulated as a topical solution, spray, mist, drops, infusion or instillation containing 0.001–10% by weight of the noble metal. 
     
     
       14. The method as set forth in  claim 12 , wherein the noble metal is nanocrystalline silver. 
     
     
       15. The method as set forth in  claim 12 , wherein the noble metal is silver, formed as a composite with oxygen. 
     
     
       16. The method as set forth in  claim 12 , wherein the noble metal is in a powder form and is delivered directly to a locus of the disease condition. 
     
     
       17. The method of  claim 16 , wherein the powder is sized with particulates no larger than 2 μm. 
     
     
       18. The method of  claim 16 , wherein the powder is sized with particulates no larger than 1 μm. 
     
     
       19. The method of  claim 18 , wherein the noble metal is nanocrystalline silver. 
     
     
       20. The method of  claim 18 , wherein the noble metal is nanocrystalline silver, formed as a composite with oxygen. 
     
     
       21. A method of treating excessive release of one or more matrix metalloproteinases from an inflammatory cell in a disease condition in a human or an animal, which comprises:
 contacting the cell with a therapeutically effective amount of an antimicrobial metal in a crystalline form characterized by atomic disorder, or with a solution derived therefrom, to provide a modulating effect on one or more matrix metalloproteinases, wherein the antimicrobial metal is formed with sufficient atomic disorder, such that the metal, in contact with an alcohol or water-based electrolyte, releases atoms, ions, molecules, or clusters of at least one antimicrobial metal at a concentration sufficient to provide a localized anti-MMP effect. 
 
     
     
       22. The method according to  claim 21 , further comprising providing a modulating effect on one or more cytokines. 
     
     
       23. The method as set forth in  claim 22 , wherein the antimicrobial metal is silver. 
     
     
       24. The method as set forth in  claim 23 , wherein the antimicrobial metal is nanocrystalline and is formed with sufficient atomic disorder such that, in contact with an alcohol or water based electrolyte, the antimicrobial metal releases ions, atoms, molecules or clusters of the antimicrobial metal on a sustainable basis. 
     
     
       25. The method as set forth in  claim 24 , wherein the one or more matrix metalloproteinases are selected from the group consisting of collagenases, gelatinases, stromelysins, and stromelysin-like matrix metalloproteinases. 
     
     
       26. The method as set forth in  claim 25 , wherein the one or more matrix metalloproteinases is a gelatinase. 
     
     
       27. The method as set forth in  claim 26 , wherein the gelatinase is MMP-9. 
     
     
       28. The method as set forth in  claim 27 , wherein the cytokine is TNF-α. 
     
     
       29. The method as set forth in  claim 28 , wherein the antimicrobial metal is nanocrystalline silver. 
     
     
       30. The method as set forth in  claim 28 , wherein the antimicrobial metal is silver, formed as a composite with oxygen. 
     
     
       31. The method as set forth in  claim 28 , wherein the one or more antimicrobial metals are provided as a coating on, or filler in, a dressing or a hydrated dressing, or in a pharmaceutical composition with one or more pharmaceutically and dermatogically acceptable carriers, diluents, or excipients suitable for topical application. 
     
     
       32. The method as set forth in  claim 31 , wherein the pharmaceutical composition includes a nanocrystalline powder of one or more antimicrobial metals, or a solution containing dissolved species from a nanocrystalline powder or coating of one or more antimicrobial metals. 
     
     
       33. The method as set forth in  claim 32 , wherein the pharmaceutical composition is a gel, cream, lotion, paste, or ointment containing the antimicrobial metal powder in an amount of 0.01–10% by weight, or a liquid formulated as a topical solution, spray, mist, drops, infusion or instillation containing 0.001–10% by weight of the antimicrobial metal. 
     
     
       34. The method as set forth in  claim 32 , wherein the antimicrobial metal is nanocrystalline silver. 
     
     
       35. The method as set forth in  claim 32 , wherein the antimicrobial metal is silver, formed as a composite with oxygen. 
     
     
       36. The method as set forth in  claim 32 , wherein the antimicrobial metal is in a powder form and is delivered directly to a locus of the disease condition. 
     
     
       37. The method of  claim 36 , wherein the powder is sized with particulates no larger than 2 μm. 
     
     
       38. The method of  claim 36 , wherein the powder is sized with particulates no larger than 1 μm. 
     
     
       39. The method of  claim 38 , wherein the antimicrobial metal is nanocrystalline silver. 
     
     
       40. The method of  claim 38 , wherein the antimicrobial metal is nanocrystalline silver, formed as a composite with oxygen.